Over the last 20 years there has been a growing awareness of the importance of the use of ionically and osmotically balanced irrigation solutions during intra-ocular surgeries. Originally, all that was available for this purpose was simple sterile saline. While saline was useful as an irrigating solution it was subsequently recognized that the lack of proper salt balance was damaging to the intra-ocular tissues. Over the years different formulations for irrigating solutions had been developed in an attempt to provide more physiologically compatible solutions.
A big advance from simple saline solution was the introduction of phosphate buffered solutions which provided both osmotic balance and pH control. While phosphate buffered saline solutions represented a major step towards less toxic irrigation fluids, they were not completely physiologic and thus produced some cytotoxic effects since they did not contain the requisite balance of salts.
Phosphate buffered saline was soon replaced by balanced salt solutions which were both ionically and osmotically balanced. In addition to sodium chloride, these solutions contained potassium chloride, calcium chloride, magnesium chloride, sodium acetate and sodium citrate. Such balanced salt solutions were judged to be more physiologically compatible with ocular tissue than simple saline or phosphate buffered saline solutions since they contained the essential ions for normal cell metabolism. Various publications in the medical literature have demonstrated the superiority of balanced salt formulations over simple saline or phosphate buffered saline solutions, such as:
1. Edelhauser, H. F., Van Horn, D. L., Hyndiuk, R. A., Schultz, R. O., "Intraocular Irrigating Solutions: Their Effect on the Corneal Endothelium," Arch. Ophthalmol., 93: 648, 1975. PA1 2. Edelhauser, H. F., Van Horn, D. L., Schultz, R. O., Hyndiuk, R. A., "Comparative Toxicity of Intraocular Irrigating Solutions on the Corneal Endothelium", Am. J. Ophthalmol., 81: 473, 1976. PA1 3. Moorhead, L. C., Redburn, D. A., Merritt, J., Garcia, C. A., "The Effects of Intravitreal Irrigation During Vitrectomy on the Electroretinogram," Am. J. Ophthalmol., 88: 239, 1979. PA1 "The cells require electrolytes. If these electrolytes are not present, one start[s] to see toxicity or apparent toxicity and cellular changes. The absence of calcium caused by viscoelastic substances is a major potential problem. PA1 `All of the currently available viscoelastics are made in calcium-free solvents. That apparently is necessary because of the stability of the viscoelastic preparations. If calcium is present in the formulation then it is apparently difficult to maintain the substances in solution, so calcium is removed. PA1 `We're facing a situation where not only calcium, but magnesium and other critical ions are not present. The cells can do fine without nutrients for a short period, but they don't do well without the ions." PA1 a. Healon--each ml of Bealon contains 10 mg of sodium hyaluronate, 8.5 mg of sodium chloride, 0.28 mg of disodium dihydrogen phosphate dihydrate, 0.04 mg of sodium dihydrogen phosphate hydrate and q.s. water for injection USP. PA1 b. Amvisc--each ml of Amvisc contains 10 mg of sodium hyaluronate adjusted to yield approximately 40,000 centistokes, 9.0 mg of sodium chloride and sterile water for injection USPQS. PA1 c. Viscoat--each 1 ml of Viscoat solution contains not more than 40 mg of sodium chondroitin sulfate, 30 mg sodium hyaluronate, 0.45 mg sodium dihydrogen phosphate hydrate, 2.00 mg disodium hydrogen phosphate, 4.3 mg sodium chloride (with water for injection USP grade, qs). PA1 BSS is a sterile physiological balanced salt solution of sodium chloride (NaCl), potassium chloride (KCl), calcium chloride (CaCl.sub.2.2H.sub.2 O), magnesium chloride (MgCl.sub.2.6H.sub.2 O), sodium acetate (C.sub.2 H.sub.3 NaO.sub.2.3H.sub.2 O), and sodium citrate dihydrate (C.sub.6 H.sub.5 Na.sub.3 O.sub.7.2H.sub.2 O). BSS is isotonic to the tissues of the eyes. It is a lint-free solution containing essential ions for normal cell metabolism. Each ml contains sodium chloride 0.64%, potassium chloride 0.075%, calcium chloride 0.048%, magnesium chloride 0.03%, sodium acetate 0.39%, sodium citrate 0.17%, sodium hydroxide and/or hydrochloric acid (to adjust pH), and water for injection.
In the development of visco-elastic hyaluronate formulations as medical devices for ophthalmic surgical procedures, it is important that they contain a physiologic balance of salt to minimize toxicity. Although the importance of such a physiologically balanced visco-elastic formulation is well recognized among the ophthalmic community, as of yet none of the commercially available hyaluronate products provide complete physiologic balanced formulations. Dr. James McCulley in Ocular Surgery News, August, 1987, summarizes the importance of physiologic balanced media as follows:
Three commercially available hyaluronates for use in ophthalmic surgery are as follows:
Denlinger, J. L., et al., "Replacement of the Liquid Vitreus with Sodium Hyaluronate in Monkeys," Exp. Eye Res. (1980) 31, 81-99, 101-117, disclose that Healon contains sodium hyaluronate (10.+-.1 mg/ml) "dissolved in a physiological balanced salt solution" (0.145 mg/ml NaCl, 0.34 mg/ml NaH.sub.2 PO.sub.4 ; and 1.5 mg/ml Na.sub.2 HPO.sub.4 ; pH=7.2.+-.0.2). The term "balanced salt solution" thus refers to an isotonic saline buffered with phosphate.
None of these three products contained the essential ions, in particular magnesium and calcium, which are judged critical for physiologic compatibility. Without these essential ions there can be significant cytotoxicity to the corneal endothelium (corneal cells).
There is available a balanced salt solution marketed by Alcon Labs which is a physiologic irrigation solution for use during various surgical procedures of the eye, ear, nose and/or throat and is listed in the 1988 PDR for ophthalmology as:
The above % may be converted to mg/ml by multiplying each by 10.
The above balanced salt solution has never been used or suggested for use with sodium hyaluronate.
Until now, where it has been attempted to prepare sodium hyaluronate in a balanced salt solution containing calcium ion and magnesium ion, it has been found that the sodium hyaluronate solution was not stable.